Tyra Biosciences, Inc. (TYRA) Earnings Call Transcript & Summary

Hello, I'm Todd Harris, of Tyra Biosciences. I'll be making some forward-looking statements today. So please be advised. Tyra is a company that's focused on making small molecule precision medicine, largely in the space of the FGFR family. We do this with homegrown chemistry, built out of our SNAP chemistry design platform. And why focus on the FGFR family? This is a really big opportunity. FGFR family members drive a number of cancers. FGFR3 in particular, is one of the largest patient populations in bladder cancer that is, in fact, driven by alterations in this gene. Additionally, in skeletal dysplasias, there are several indications, including achondroplasia that are FGFR3-driven. And TYRA-300 is a selective molecule, initially developed for oncology, but with some really exciting data that we presented last year in a preclinical model of achondroplasia, we also expanded the indication of interest here as well. And what we're showing here is an animal model from Laurence Legeai-Mallet in Paris, a model that has an alteration, recapitulating the achondroplasia phenotype and a significant improvement with treatment on TYRA-300 in this model. That caused us to move quickly forward with a planned IND submission for a Phase II in achondroplasia in the second half of this year that we're on track to [indiscernible]. As well as this year, you can expect, in the second half, reading out our first data cut from a Phase I study with TYRA-300 in a late-line metastatic patient population. We also have TYRA-200 that's in the clinic now in cholangiocarcinoma, FGFR2 positive as well as TYRA-430, which is a new clinical development candidate that's moving forward in IND-enabling. We'll talk -- start today by talk about the achondroplasia opportunity, which is really an efficient development path for TYRA-300 in a really attractive market. Achondroplasia, the short stature condition is actually driven by an alteration at G380R, this causes overactivity of FGFR3, where the primary function is in chondrocyte proliferation and differentiation actually acts as a break on those. And so when it's overactive, you have the phenotype emerge of short stature. You also have a number of other clinical complications. At a young age, a really serious complication of foramen magnum stenosis. And as children age, pain, multiple surgeries, including back surgeries and other functional limitations become key challenges. There is one agent, vosoritide, that has an accelerated approval today. This is based off of 1- and 2-year annualized height velocity metrics that showed an improvement from baseline, which is typically 4 centimeters in this patient population, especially between the ages of 5 to 12. And they move that up into the mid-5s, gaining about 1.5 centimeters in long-term follow-up studies. But that's still significantly underperforming relative to target, which would be on average, about 7.6 centimeters per year when you look at kids that grow from age 1-plus. Most recently, they reported out 7-year data from their Phase II showing about a 4-inch improvement after 7 years of treatment. The real gap here from final height of kids with achondroplasia versus average static individuals can be 16 to 18.5 inches, so there's really an opportunity to do more. Now very recently, BridgeBio read out 12-month data with a low dose of infigratinib, showing similar results in terms of performance on annualized height velocity, which is a really encouraging outcome demonstrating that direct inhibition with FGFR3 can drive improvements. But in terms of FGFR3 engagement, we believe that more potent engagement of this target could do better. And we think the best evidence of that is from some of the more recent work as well with vosoritide in kids with short stature that's driven by EMP [indiscernible], the target by which they work, where they're seeing about 18.5 centimeter per year improvement in AHV -- by treating with AHV. And so that's the target we think about when we really engage FGFR3 the right way. Infigratinibs used at a low dose, and it's used at a low dose, largely to avoid complications that come because it's a pan-FGFR inhibitor has equal activity for FGFR1/2/3. And that's really clear from some of the preclinical data that they showed, when used at a high dose in the animal model I referenced earlier, Pemigatinib sees a really nice result in terms of long bone elongation. But this is a dose that's more equivalent to about half of their oncology dose. And it's a dose where hyperphosphatemia was seen in their Phase I study really preventing them from going this high. A follow-up study at a lower dose showed some improvement, about half as much, but statistically significant. And it was really this that led them to go ahead and explore doses in this lower range and selected dose most recently that they're moving into Phase III. But we think this is really clear evidence that hitting the target harder with an FGFR3 specific doesn't -- that has a wider therapeutic index by avoiding FGFR1 as an opportunity. And that's essentially what we see as the opportunity for TYRA-300. We saw really good results at 1.2 mg per kg. This is a dose that we think we have a therapeutic index for based off of the preclinical modeling that we've done. And it's really avoiding what we see when you use oncology level doses in patients with oncology that come from hitting the other isoforms. With FGFR1 engagement, you see hyperphosphatemia in the vast majority of these patients. With FGFR2 engagement, you see a lot of ocular tox. You see some really debilitating nail tax. With FGFR4 engagement, you can see diarrhea. That's led to most of these pan-FGFR inhibitors that are approved, seen dose reductions and discontinuations when used at full oncology doses. And that really caused us to work on TYRA-300 when we kicked off the company 6 years ago. And we used our SNAP chemistry platform in a highly iterative approach with crystallography that we did rapidly across the FGFR isoforms to identify a dose -- or to identify a compound, sorry, that is specific for FGFR3 and spares the others. And you see that in our preclinical data. What I'm showing here are cellular BAF III data, the IC50s for BAF III that are driven by either FGFR1/2/3/4. And shown here are the pan-FGFR inhibitors, including Infigratinib and the activity for FGFR3, which is really potent, TYRA-300 is also really potent here. But when we look at FGFR2, all of the other compounds are very potent. TYRA-300 starts to back off significantly from its activity in order of magnitude. You see the same effect with FGFR1, the same effect with FGFR4. And this gives us the confidence as we go into the clinic, sparing these other isoforms could potentially improve the tolerability and allow us to really hit the target the right way for achondroplasia. So as we follow up with the -- what we saw in the animal model, we saw really compelling results at the dose used in terms of normalizing skull length, skull width, normalizing the foreman magnum length and width. And when we looked at the histopathology, we saw a remarkable result in normalizing bone architecture. This is what typical femur growth pace looks like. You have the secondary [indiscernible] center and the proliferating chondrocytes. With the FGFR3 mutant phenotype, the achondroplasia phenotype that secondary [indiscernible] center nearly goes away entirely. And with treatment, you see this restoration of that normal architecture. So as we move into the clinic, we're really focused first on the needs of the achondroplasia community, individuals with achondroplasia have to go through daily adaptations to live in a world that's largely built for average stature individuals. And you see this across multiple areas where there's restricted reach, restricted stride as one example. When you think about driving a car, individuals with achondroplasia have to often turn off the airbags because of their limited reach makes it unsafe for them to have them on. Surgeries are something that emerge pretty frequently and early in life with disabling pain. And a lot of this is focused on really spinal stenosis, where you have impingement of the spinal canal due to some of the architecture of the back with this alteration. FDA has made it really clear that they want companies like us, while initially, we can focus on annualized height velocity as a surrogate, it's really final height and other clinically meaningful endpoints that would lead to confirmatory approval. This is why vosoritide today has an accelerated approval and are continuing to follow individuals out to final height. And a lot of this actually comes out of human growth hormone context where the first year AHVs were really compelling but they saw a significant decrease in that. So as we start to look at vosoritide and BridgeBio data that goes out 12 and 18 months and see that persist, albeit modestly, it's encouraging that, that can lead to long-term benefits. And we see the same opportunity with TYRA-300. So we'll initially focus on AHV at 6, 12 and 24 months as an important surrogate but go through all the exploratory endpoints in terms of functional improvements, clinical sequela and follow kids out to final heights. We're going to do this initially with a sentinel dosing in an open-label cohort as we kick off the Phase II, move quickly up in doses that we think will be efficacious and then choose the dose to move into a randomization phase where we might choose one or more doses ultimately to compare to a control. Achondroplasia is just one of the opportunities, FGFR3-driven short stature, there's also hypochondroplasia and other more severe conditions driven by FGFR3 alterations. And there's also other genetic short stature conditions that are FGFR3-related like, Leri-Weill Dyschondrosteosis, where shocked mutations control the expression of FGFR3 and pediatric short stature as well. So really a large number of opportunities in terms of where we can expand with agent TYRA-300. Now additionally, we continue to pursue a really exciting opportunity in oncology. And here, it's all about improving the tolerability and durability over the pan-FGFR inhibitors that are being used today. One additional and important functional characteristics of TYRA-300 is that was designed to avoid an important acquired resistance mutation at the gatekeeper. You can see erdafitinib pictured here in the active side of the FGFR3 protein. And in the back of the pocket here, you have this gatekeeper mutation where this dimethoxyphenyl chemistry reside that essentially causes the [ molecule ] no longer be potent. And all of the pan-FGFR inhibitors have shared the same dimethoxyphenyl inside for this limitation. This is the type of limitation that was seen with the early EGFR inhibitors of gefitinib and erlotinib, and was overcome by chemistry with osimertinib that avoided the back pocket. And that actually led to a PFS benefit. And as we look across targets, this type of acquired resistance mutation at the gatekeeper or solvent front that emerges continues to highlight that chemistry that is built to avoid those areas of the pocket that can mutate lead to a really nice improvement in PFS. Where we look at FGFR3, FGFR 2 targets, we're really just at the first stage of first-gen compounds with more limited durability that could be improved. And as we look at the size of the opportunity for an FGFR3 inhibitor in urothelial cancer, reference what we see with osimertinib is a market opportunity, which is in lung cancer that's EGFR-positive. It's a relatively large patient population, 30,000 new patients a year. Most of these patients are now seen an EGFR inhibitor through multiple clinical studies that have advanced the lines of therapy. And the average patient is on drug for 23 months. That led to 23 sales of $5.8 billion with this drug. Other important targets like ALK and RET have smaller patient populations and more modest market opportunities, but nonetheless attractive. When we look at the FGFR3 opportunity, it's actually a bigger patient population than what we see with osimertinib. But erdafitinib, the one approved drug is really only scratched the surface by getting an approval in late line, second line or later metastatic patients and only having about a 5-month durability. Do you see this massive gap and a lot of that is actually driven by [indiscernible] bladder cancer, where there's a lot of FGFR3 positivity. And where we think time on therapy could be significantly extended and a lot of benefit essentially accrued to patients as a result. The key to getting there though, as has been with EGFR ALK and RET is next-generation chemistry, avoiding the gatekeeper and improving selectivity, which is exactly how we built TYRA-300 to achieve. You see that in the enzymatic IC50, we ran a full KINOMEscan, and we follow up with targets with 90% coverage or more. And you see that FGFR3 is the most potent target for this molecule, and quickly behind it are the other FGFR isoforms but several full difference enzymatically. And as I mentioned, cellularly, orders of magnitude differences that emerge when you compare the FGFR3 activity to its FGFR1/2/4. And this is a key differentiation again, over the approved agents that are being studied or in development agents that are being studied, both achondroplasia and oncology. We see the follow-up or the benefit from avoiding FGFR by avoiding hyperphosphatemia in a 24-hour single dose experiment in a rat where erdafitinib, you see with dose escalation increases phosphate levels, whereas TYRA-300 remains consistently low. We also see in cellular assays, this benefit of avoiding the gatekeeper. In gray is the FGFR3 wild-type activity. We're looking at enzymatic IC50s linearly. And those dots show the loss of activity that emerges when you have a gatekeeper mutation. TYRA-300 is essentially agnostic to this mutation that arises clinically with equal activity. And we can show how that benefits -- potentially benefits the drug and looking at TYRA-300 performance on this particular bladder cancer xenograft, this is a FGFR3 TACC3 fusion, where TYRA-300 performs really well in shrinking tumors. Erdafitinib performs well as well. But if we crisper in the gatekeeper mutation that's been seen in patients or to fit it loses its activity, whereas TYRA-300 retains that activity. We see really great performance in the S249C activating mutation, bladder cancer model. We're at lower doses than erdafitinib, we see tumor shrinkage. And so that really highlights the therapeutic index that we have been building in here, where we can, at a low dose, see tumor shrinkage and avoid the hyperphosphatemia, as I highlighted in that rat experiment. We're now in a clinical study. We're going to be reading out the first set of data from this study in the second half of the year. We finished Part A, which was an all-comers patient population moving quickly with the goal of seeing an MTD. We actually completed this without getting to an MTD, what that means is we saw essentially what we would hope to see is that we were at a dose that we didn't need to go any further above to ensure that we are hitting FGFR3 and that we could then focus on a set of doses below that where we could really dial in the right dose to hit FGFR3 optimally and avoid and reduce any tolerability or toxicity effects as best as possible. So that involves multiple Part B doses. In Part B, we're treating FGFR3-positive patients only, and it will be both Part A and Part B data that we'll be talking about in the fall. To highlight the opportunity, I mentioned how NMIBC is really where most of the FGFR3-positive patients are intermediate risk, in particular, where we're talking about 50,000 patients that are potentially addressable. And the vast majority of these patients are FGFR3 positive. That means that they have one of these five mutations on the right, either an alteration that swaps an amino acid to assisting, so that a homodimer essentially can form a disulfide bridge that causes constitutive activation or an FGFR3 TACC3 fusion, which essentially does the same thing. These can be detected by liquid biopsy, next-generation sequencing pretty readily, whether that's blood, urine or tissue. And so we have a really compelling data set that J&J has put up with looking at erdafitinib in a number of different treatment patient populations. We'll start with where they have a full approval, and that's in second and third-line metastatic urothelial, an ORR of about 35% and 12 months overall survival. Our target with TYRA-300 is to hit this level, if not more, initial efficacy in terms of ORR because the real key limitation here that we see is that patients really struggle to stay on drug due to tolerability. And so we think we have an opportunity for a more durable result. If we have that efficacy but improved tolerability. Erdafitinib has also moved into this high risk and intermediate risk non-muscle invasive bladder cancer space. And in several patients in intermediate risk, you're seeing a really nice chemo ablative results, a complete response of 83%. That's with treatment of about 3 months. Most patients really struggle to tolerate the drug and come off of it. As a result, J&J has discontinued looking at oral erdafitinib in this patient population. That's despite actually a lower dose, about a 33% lower dose than was used in the metastatic setting. And is now prioritized what's called the [indiscernible], which is essentially a drug-eluting stent that gets inserted every 3 months into the bladder to try and localize the effect. This oral opportunity is really what we see with TYRA-300, and it's a really big opportunity for us and it's coming out of our [indiscernible] key target to open up both an NMIBC as well as a late-line metastatic Phase II to advance the dug and the compound. So with that, this is a snapshot. We're relatively well capitalized at $382.5 million in the bank. Coming up next is going to be our Phase I data in the second half of the year and is planned to submit an IND for achondroplasia Phase II in the second half as well as completing IND-enabling studies for a new compound TYRA-430. And so with that, I'll finish. Any questions? All right. Thank you very much.